The use of neurostimulation, including deep brain stimulation, and modulation of neural structures for both the excitation and inhibition of the neural elements, provides an effective alternative to today's surgical lesioning techniques in the treatment of sleep disorders. Today's surgical lesioning techniques, while technologically improved and more precise, have the fundamental limitation of being inherently irreversible and are essentially a “one shot” procedure with little chance of alleviating or preventing potential side effects. In addition, there is a limited possibility to provide continuous benefits as the disorder progresses and the patient's symptoms evolve.
It has been recognized that electrical stimulation holds significant advantages over lesioning in the treatment of various disorders, inasmuch as lesioning can only destroy nervous system tissue. In many instances, the preferred effect is to stimulate to increase, decrease, or block neuronal activity. Electrical stimulation permits such modulation of the target neural structures and, equally importantly, does not require the destruction of nervous tissue. In many ways, this is analogous to a reversible and adjustable lesioning procedure.
Sleep is an active process during which many body functions fluctuate, including respiration, temperature, body tone and hormone secretion. A specialized type of sleep, Rapid Eye Movement (REM sleep) is associated with dreaming, fleeting eye movements, muscle twitching, a generalized decrease in body tone, and irregular respiration, heart beat and blood pressure.
It is believed that up to 20% of the general population have sleep disorders. Sleep disorders can include narcolepsy and its clinical manifestations such as sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations; insomnia; sleep apnea; hypersomnia; and related disorders. Narcolepsy is a particularly dangerous problem given its incidence of 0.05% in the U.S. population, according to the American Association of Sleeping Disorders.
The Circadian Cycle
Inventions of the light bulb and airplane have greatly enhanced human capability. However, they have also imposed new challenges to human health. Travel across time zones and shift-working schedules are familiar examples of such challenges. Jet lag is often associated with fatigue, daytime sleepiness, loss of appetite, difficulty concentrating, and inability to sleep at night. These symptoms are experienced because the human body is genetically programmed to perform certain physiological functions only at certain times of the day. The variation of physiology around the 24-hour cycle is referred to as circadian rhythm, which is an important behavioral adaptation to the earth's daily rotation.
Circadian rhythms are not merely passive reflections of the environmental light-dark cycle, but instead depend upon an underlying endogenous clock. The suprachiasmatic nucleus (SCN) of the hypothalamus is the mammalian circadian clock that synchronizes the functions of different organ systems to each other and to the environmental light-dark cycle. In addition to the SCN, other structures also influence the human circadian rhythm. The retina is the dominant circadian clock in invertebrates, such as sea slugs. The pineal gland is the dominant circadian clock in birds. In mammals, these ancient circadian pacemakers work in concert with the SCN. Melatonin is a hormone synthesized in the pineal gland and released at night.
Serotonin is an important neurotransmitter involved in the mechanisms related to the generation of the different stages of awakeness-sleep cycle. (Khateb, A. et al., Pharmacological and morphological evidence for a serotoninergic input to cholinergic nucleus basalis neurons. Eur. J. Neurosci, v5, p 541-47, 1993). Previous research has proven that lesions in the Raphe Nucleus, which is rich in serotonin, can produce intense insomnia which is reversed with the injection of serotonin precursors (5-hidroxitriptofano) (Jouvet, M., The role of monoamine and acethylcholine-containing neurons in the regulation of the sleep-waking cycle. Ergebn. Physiol V 64, 165-307, 1972).
It is also known that the serotoninergic fiber (Khateb et al. 1993), which originates from the Raphe Nucleus, together with the noradrenergic fibers, is tonic activated during the alert phase, decreasing its activity during non-REM sleep and remaining silent in REM sleep (Jacobs, B. L.; Fornal. C. A., Activity of brain serotoninergic neurons in the behaving animal. Pharmacol. Ver. 43, 563-78, 1991). Khateb et al. (1993) proved that serotoninergic neurons hyperpolarize colinergic neurons in the Basal Forebrain and noradrenergic neurons promote depolarization of the same neurons located in the Basal Forebrain.
Jouvet et al. in 1984 described a region just ventral to the Locus Coeruleus which lesion causes total inhibition of the motor behavior during the dreams. (Jouvet, M. et al., Etude de la privation selective de la phase paradoxale de sommeil chez le chat. Comptes Rendus de la Societe de Biologie, Paris, 1984.) Later, Sakai named it the Perilocus Coeruleus region or Alfa-Coeruleus nucleus (Sakai, K., Central mechanisms of paradoxical sleep. Brain Development 8, 402-7, 1986.) The lesion of this region cancels the inhibition of the motor neurons during REM sleep and releases the motor manifestation during the dreams (Jouvet et al., 1972).
The Locus Coeruleus and other nuclei located in the posterior portion of the brainstem which are identified infra, have been studied as possible targets. (Gonzalez-Martinez, J A, Doctorate Thesis: Study of the electroscilograms of the olfactory tract of the rat during the awakefull-sleep cycle. University of Sao Paulo Medical School, Sao Paulo, 2002; Jacobs, B. L. and Fornal, C. A., 1991; Jouvet, M., 1972; Jouvet, M, Recherches sur les structures nerveuses et les mecanismes responsables des differentes phases du sommeil physiologic. Arch. Ital. Biol. V100, 125-206, 1962; Jouvet, M.; Vimont, P; Delorme, F. Etude de la privation selective de la phase paradoxale de sommeil chez le chat. Comptes Rendus de la Societe de Biologie, Paris, 1984; Khateb, A. et al., 1993; Kleitman, N., Sleep and Wakefulness. Chicago, The University of Chicago Press, 1963; Moruzzi, G., The sleep-waking cycle. Ergebn Physiol v 64 1-165, 1972; Pompeiano, O., Mechanisms responsible for spinal inhibition during desynchronized sleep: Experimental study. In Guilleminauult, C; Dement, W C; Passouant, P (ed), Advances in Sleep Research, v.3, New York, Spectrum, p 411-49, 1976; Sakai, K., 1986; Sakai, K; El Mansari, M; Lin, J. S; Zhang, G; Vanni-Mecier, The posterior hypothalamus in the regulation of wakefulness and paradoxical sleep. In Mancia, G (ed), The Diencephalon and Sleep, New York, Raven Press, 171-98, 1990; Steriade, M; Datta, S; Pare, D; Oakson, G; Curro Dossi, R., Neuronal activities in the brain stem cholinergic nuclei related to tonic activation processes in thalamocortical systems, J Neurosci, 20, 2541-59, 1990; Steriade, M. and McCarley, R W, Brainstem control of wakefulness and sleep. New York and London, Plenum Press, 1990; Steriade, M. et al., Thalamocortical oscilations in the sleeping and aroused brain. Science, 226, 679-85, 1993; and Webster, H. and Jones, B E, Neurotoxic lesions of the dorsolateral pontomesencephalic tegmentum-cholinergic cell area in the cat. Effects upon sleep-waking states. Brain Res, 458, 285-302, 1988.)
Narcolepsy
Narcolepsy is a disabling illness affecting more than 1 in 2,000 Americans. Most individuals with the disorder are not diagnosed, and are thus, not treated. The disease is principally characterized by a permanent and overwhelming feeling of sleepiness and fatigue. Other symptoms involve abnormalities of dreaming sleep, such as dream-like hallucinations and finding oneself physically weak or paralyzed for a few seconds.
Studies have shown that even treated narcoleptic patients are often markedly psychosocially impaired in the area of work, leisure, interpersonal relations, and are more prone to accidents. These effects are even more severe than the well-documented deleterious effects of epilepsy when similar criteria are used for comparison.
The large majority of narcoleptic patients in this country are still undiagnosed, and narcoleptic subjects are most often diagnosed only after many years of struggle. In one recent study, the mean number of years between the onset of symptoms and correct diagnosis was 14 years. Since the symptoms of narcolepsy usually appear during adolescence, this means that most narcoleptic patients are diagnosed too late to prevent the dramatic impact of the disease on their personal and professional development.
The main symptoms of narcolepsy are excessive daytime sleepiness and abnormal REM sleep, i.e., intrusion of REM sleep into the waking state or into the transition periods between waking and sleep. Many narcoleptics are sleepy during most or all of the day, specifically during times when normal people may only have a tendency to become somnolent. An example would be the tendency of a normal person to become somnolent after a heavy meal, whereas a narcoleptic would fall asleep.
Patients with narcolepsy are subject to narcoleptic sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations; however, an individual patient may not have all these symptoms. Sleep attacks may occur at any time the day and in embarrassing and dangerous situation, such as while walking, climbing a ladder or even driving. These attacks are brief but can occur anytime and in any situation. Narcolepsy is not only a serious and common medical problem, it also offers basic sleep researchers a unique opportunity to gather new information on the central mechanisms regulating REM sleep and alertness. Since the 1960s it has been known that several of the disabling symptoms of narcolepsy, such as sleep paralysis, cataplexy and hypnagogic hallucinations, are pathological equivalents of REM sleep.
Sleep paralysis, it is the loss of tone, such as that which occurs during an episode of REM sleep, but it occurs when the patient is awake. Its consequences are relevant and extremely dangerous. A frightening symptom considered to be an abnormal episode of REM sleep atonia, the patient suddenly finds himself unable to move for a few minutes, most often upon falling asleep or waking up. During hypnagogic hallucinations, patients experience dream-like auditory or visual hallucinations, while dozing or falling asleep. Cataplexy, a pathological equivalent of REM sleep atonia unique to narcolepsy, is a striking, sudden episode of muscle weakness triggered by emotions. Cataplexy is characterized by loss of body tone without loss of consciousness. Typically, the patient's knees buckle and may give way upon laughing, elation, surprise or anger. In other typical cataplectic attacks the head may drop or the jaw may become slack. In severe cases, the patient might fall down and become completely paralyzed for a few seconds to several minutes. Reflexes are abolished during the attack.
Narcolepsy can be diagnosed using specific medical procedures. The diagnosis of narcolepsy is usually easy if all the symptoms of the illness are present. More often, however, the symptoms of dissociated REM sleep such as cataplexy are mild. In such cases, a nocturnal polysomnogram, followed by the multiple sleep latency test (MSLT), is suggested. This test, performed at a sleep disorders clinic, will confirm the daytime sleepiness by showing a short sleep latency of usually less than 5 minutes, as well as an abnormally short latency prior to the first REM period (SOREMPs). Other causes of daytime sleepiness, such as sleep apnea or periodic leg movements, are also excluded by the nocturnal recordings.
In the current treatment of narcolepsy, no single therapy will control all the symptoms. The narcolepsy responds best to strategically placed 15 to 20 minutes naps and the use of stimulants drugs (e.g., dextraamphetamine sulfate or methylphenidate hydrochloride (Ritalin), or pemoline) and a tricyclic antidepressant (e.g., imipramine or clormipramine). The combined use of these stimulants and tricyclic antidepressant drugs is often indicated. The occurrence of tolerance is frequent and the treatment fails quite often. Moreover, the stimulants drugs and the tricyclic antidepressants increase the level of cathecolamines, and their chronic administration may produce hypertension.
Sleep Apnea
Sleep Apnea is a disorder of breathing during sleep. Typically it is accompanied by loud snoring. Apnea during sleep consist of brief periods throughout the night in which breathing stops. People with sleep apnea do not get enough oxygen during sleep. There are two major types of apnea: obstructive sleep apnea and central sleep apnea.
Obstructive sleep apnea is the most common type and is due to an obstruction in the throat during sleep. Bed partners notice pauses of approximately 10 to 60 seconds between loud snores. The narrowing of the upper airway can be a result of several factors including inherent physical characteristics, excess weight, and alcohol consumption before sleep.
Central sleep apnea is caused by a delay in the signal from the brain to breath. With both obstructive and central apnea, the subject suffering therefrom must wake up briefly to breathe, sometimes hundreds of times during the night. Usually there is no memory of these brief awakenings. This type of sleep apnea can be treated with electrical stimulation of the above-mentioned nuclei.
The treatment of sleep apnea is governed by the severity of symptoms and the type of apnea (central or obstructive). In central apnea, trazadone has been reported to have some effects on the treatment of the symptoms. Other medications may include acetazolamide, theophylline and clomipramine, which have produced questionable results.
Insomnia
Insomnia is a sleep disorder that comes in many different manifestations and symptoms, including difficulty falling asleep, no problem falling asleep but difficulty staying asleep, i.e., many nocturnal awakenings, or even waking up too early. Normally a normal adult without any stress factors needs from 7 to 9 hours of good quality of sleep; the actual amount of sleep needed varies from person to person.
There are three basic types of insomnia: 1) transient insomnia, which last for a few nights; 2) short-term insomnia, in which poor sleep lasts from two to four weeks of poor sleep; and 3) chronic insomnia, in which poor sleep occurs most nights and may last a month or longer.
Transient and short-term insomnia generally occur in people who are temporarily experiencing one or more of the following: stress, environmental noise, extreme temperatures, change in the surrounding environment, sleep/wake schedule problems such as those due to jet lag or medication side effects, for example.
Chronic insomnia is more complex and often results from a combination of factors, including underlying physical or mental disorders. One of the most common causes of chronic insomnia is depression. Other underlying causes include arthritis, kidney disease, heart failure, asthma, sleep apnea, restless legs syndrome, Parkinson's disease, and hyperthyroidism. However, chronic insomnia may also be due to behavioral factors, including the misuse of caffeine, alcohol, or other substances; disrupted sleep/wake cycles as may occur with shift work or other nighttime activity schedules; and chronic stress.
Treatment of Transient and Short-Term Insomnia
Transient and short-term insomnia may not require treatment since episodes last only a few days at a time. For example, if insomnia is due to a temporary change in the sleep/wake schedule, as with jet lag, the person's biological clock will often get back to normal on its own. However, for some people who experience daytime sleepiness and impaired performance as a result of transient insomnia, the use of short-acting sleeping pills may improve sleep and next-day alertness. As with all drugs, there are potential side effects. The use of over-the-counter sleep medicines is not usually recommended for the treatment of insomnia.
Treatment of Chronic Insomnia
Treatment for chronic insomnia first consists of diagnosing and treating underlying medical or psychological problems. Further treatment includes identifying a patient's behavior(s) that may worsen insomnia and advising the patient to stop or reduce such behavior. Finally, sleeping pills may be prescribed, however, the long-term use of sleeping pills for chronic insomnia is controversial.
Jet Lag Syndrome
Jet lag, also called desynchronosis, is a temporary condition that some people experience following air travel across several time zones in a short period of time. Jet lag causes the traveler's internal clock to be out of sync with the external environment. People experiencing jet lag have a difficult time maintaining their internal, routine sleep-wake pattern in their new location, because external stimuli, such as sunshine and local timetables, dictate a different pattern. For this reason, the person experiencing jet lag can feel lethargic one moment and excited the next. Jet lag creates a double bind for vacationers and business people who must cross several time zones to reach their destination, but who are also intent on maximizing sightseeing or productivity. As travelers attempt to adjust their internal clock to a new external environment, symptoms result with varying intensity.
Jet lag occurs while rapidly crossing time zones, or, more specifically, it occurs after crossing the Earth's meridians. Meridians demarcate geographic position in relation to the Earth's poles and, ultimately, define time zones. Jet lag is a unique sleep disorder because its onset is not necessarily caused by abnormal sleep patterns, like insomnia. Therefore, travelers who sleep normally prior to transmeridian travel are not immune to jet lag. Again, the symptoms of jetlag result when a person's internal clock attempts to acclimate to a new external environment. This acclimation involves circadian rhythms that, among other functions, are associated with the body's management of sleep.
In addition to the “tired-wired,” “soar-crash” feeling that travelers experience after long, rapid air travel, there are numerous symptoms that may occur with jet lag, such as insomnia, daytime fatigue, stomachaches, headaches, irritability, and decreased awareness. The degree of disruption varies greatly among people; some may not be bothered at all. Jet lag is a transient sleep disorder and is classified differently than other, more serious disorders. Although jet lag occasionally lasts for a week or more, travelers usually return to their normal sleep-wake pattern after a day or two. For many travelers, jet lag can catalyze the effects of certain conditions associated with the head and nervous system that are not related to specific sleep-wake patterns. For example, many symptoms attributed to jet lag are actually caused by the environment of the airplane, e.g., dry air due to very low humidity in an airplane, pressurization, noise, vibrations, and a cramped environment. These symptoms may include dry eyes, dry and irritated nose and sinuses, headaches, earaches, muscle cramps, and abdominal distention (bloating). Occasionally, dizziness or swollen feet and ankles may occur.
The treatment of Jet Lag syndrome is still a matter of debate since no clear therapeutic effect has been observed with any drug or behavioral treatment. Melatonin is the hormone produced in the pituitary gland that may act “re setting” the biological clock of the hypothalamus and controlling the symptoms. Unfortunately, there is a lack of scientific data in respect of the use of this hormone in the treatment of Jet Lag or any other disease.
The causes of the above-described sleep disorders include the sudden intrusion of the REM sleep during the awake period. Hence, the rationale of the presently provided methods of treatment is to abort or activate REM sleep by modulating specific nuclei in the brain stem, depending upon the sleep disorder or abnormal awakeness-sleep cycle to be treated, as discussed infra. Several papers highlight the role of Locus Coeruleus in the generation of REM Sleep. The inhibition of this specific nucleus in experimental trials interrupts the REM Sleep and its clinical manifestations, thus controlling and avoiding the dangerous consequences of those sleep disorders. The same neurophysiological response happens when lesions are provoked in this nucleus or related nuclei.
The Locus coeruleus, a small noradrenergic nucleus, and the Nucleus Reticularis Pontis Oralis and Caudalis (NRPO and NRPOC) have been described as the main relay for the generation of REM sleep. (Jouvet, M. The role of monoamine and acethylcholine-containing neurons in the regulation of the sleep-waking cycle. Ergebn. Physiol V 64, 165-307, 1972).